Combinatorial genome editing to create enhanced biomanufacturing platforms

该项目将加强创新药物的生产，提供更可预测的成功途径，并在更加确定的情况下，能够更快、更廉价地生产改变生活的药物，给患者和经济带来宝贵的后果。重点是改进用于制造药物的系统，这些药物建立在天然分子和蛋白质的知识基础上，这些分子和蛋白质是治疗其他无法治愈的疾病的有效药物。这些分子通常被称为生物药物(或生物疗法或生物制剂)，由胰岛素代表，胰岛素是一种由较小成分(氨基酸)组成的聚合物，通过胰腺细胞中的遗传密码连接成特定的顺序。人们普遍了解胰岛素在糖尿病治疗中改变生命的后果，但它只是许多已经、正在或将要用于治疗癌症(如阿瓦斯丁)、凝血障碍(如第VIII因子)或类风湿性关节炎(如Remicade)等疾病的生物药物中的一种。这些药物中的每一种都是通过基因工程制造的，它们是由发酵罐中的哺乳动物细胞合成的。具有如此巨大潜力的药物的研究和安全性验证是漫长而昂贵的，但对患者、社会和经济的回报是巨大的。生物制药主导了药品市场，2013年，销售前十名的药品中有七种是生物制药，总销售额为580亿美元。潜在的回报是巨大的，但同样的，投资也是巨大的，因此患者和卫生机构的成本很高。人们希望使进入市场的路线更容易，更不容易失败，降低制造成本，从而降低治疗成本。这种情况因新形式的生物药物的发展而变得复杂--分子被设计成更具体、更有选择性。在治疗到目前为止无法治愈的疾病方面有效而有效。许多这样的生物药物可以设计(用于“理论”制造)，但不能由目前工业使用的细胞生产(或生产得很差)。这是当前项目中需要解决的挑战--制造用于制造大多数新兴生物制药的新版本的细胞。这种方法新颖、令人兴奋，并提供了改变生物制药商业生产的可能性的潜力。我们将设计成一个新的制造平台的细胞是中国仓鼠卵巢(CHO)细胞。据估计，目前有900种生物制药正在进行临床试验，其中70%是在CHO细胞中制造的，该项目将三个具有强大和复杂技能的不同群体结合在一起，使这一项目得以实现。首先，曼彻斯特大学的艾伦·迪克森教授定义了CHO细胞的某些方面，可以通过改变这些方面来提高生物制药生产的效率和确定性。这些目标与缩短CHO细胞达到生产规模所需的时间有关，并使细胞能够制造非天然产品(用于生产下一代生物制药)。Horizon Discovery已经建立了在细胞中添加和/或移除多个基因的技术，这项技术允许对CHO细胞进行基因工程，将CHO细胞重新设置为Dickson教授研究定义的更理想的版本。Horizon方法将允许对CHO细胞进行组合的多种改变，以开发一个包含微妙不同细胞版本的工具箱，以应对许多新的生物制药在研究阶段带来的挑战。最后，国家生物制品制造中心将采用为提高性能而设计的CHO细胞，并确定CHO细胞工具箱的潜力，以支持商业制造规模的现实生产潜力。一个强大的团队将假设转化为现实来制造。

This project will enhance the manufacture of innovative medicines, allowing for more predictable routes to success and, with added certainty, enable the production of life-changing medicines more rapidly and cheaply with valuable consequences to patients and the economy. The focus is on improvement of the systems used to make medicines built from the knowledge of natural molecules, proteins, that are potent agents for the treatment of otherwise untreatable diseases. The molecules, often referred to as biopharmaceuticals (or biotherapeutics or biologics) are represented by insulin, a polymer of smaller components (amino acids) linked into a defined order by the genetic code in cells of the pancreas. The life-changing consequences of insulin in the treatment of diabetes is universally understood however it presents but one of many biopharmaceuticals that have been, are being/will be, made to treat diseases such as cancers (e.g Avastin), blood clotting disorders (e.g Factor VIII) or Rheumatoid arthritis (e.g Remicade). Each of these medicines is made by genetic engineering and they are synthesised by mammalian cells in fermenters. The research and safety validation of medicines of such wonderful potential is prolonged and costly but the rewards, for patients, society and economy are immense. Biopharmaceuticals dominate the pharmaceutical marketplace and in 2013, 7 of the top 10 selling drugs were biopharamcetuicals with combined sales of $58 billion. Potential rewards are immense but equally the investment is significant and consequently the cost to the patient and health agencies is high. There is a desire to make the route to market easier and less susceptible failure, to bring down the cost of manufacture and, hence, treatment. This situation is complicated by the development of new forms of biopharmaceuticals - molecules designed to be more specific, selective. potent and effective in treating diseases that until now have been untreatable. Many such biopharmaceuticals can be designed (for "theoretical" manufacture) but cannot be produced (or are produced poorly) by cells currently in industrial use. This presents the challenge to be addressed in the current project - making a new version of the cell used to manufacture the majority of the emerging biopharmaceuticals. The approach is novel, exciting and offers the potential to alter what is possible in the commercial production of biopharmaceuticals. The cell we will engineer into a new manufacturing platform is the Chinese Hamster Ovary (CHO) cell. Estimates suggest that 900 biopharmaceuticals are currently in clinical trials and 70% are being made in CHO cells, The project brings together three distinct groups with strong and complentary skills to make this project occur. Firstly, Professor Alan Dickson (University of Manchester) has defined aspects of the CHO cell that can be altered to increase the efficency and certainty of production of biopharmaceuticals. These targets are associated with shortening the time it takes for CHO cells to reach manufacturing scale and enabling cells to make non-natural products (for production of the next generation of biopharmaceuticals). Horizon Discovery has built the technologies to add and/or remove multiple genes from cells, a technology that permits CHO cells to be genetically engineered to re-set the CHO cell to the more desirable version defined by the studies of Professor Dickson. The Horizon approach will enable multiple changes to be made to CHO cells, in combinations, to develop a toolbox of subtly-different cell versions to address the challenges presented by the many new biopharmaceuticals at research stage. Finally, the National Biologics Manufacturing Centre will take CHO cells engineered for enhanced performance and define the potential of the toolbox of CHO cells to support real-life manufacturing potential at commercial maunfactruing scale. A strong team to take the hypothesis to reality to manufacture.